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Introduction: Bipolar disorder (BD) is a genetically heritable mood disorder typically characterized by manic and depressive episodes. Cognitive impairments experienced by people with BD are one of the best predictors of functional capacity in their daily lives. There are notable impairments in various domains, such as executive functioning, working memory, and processing speed, in both individuals diagnosed with BD as well as their first-degree unaffected relatives, which emphasizes the important role genetic factors play in the onset and presence of cognitive impairments. One commonly studied single nucleotide polymorphism (SNP) associated with BD and cognition is the CACNA1C rs1006737 SNP. Although there have been numerous studies investigating the effects of rs1006737 on cognitive functioning in BD, results have been inconclusive and mixed. Thus, we examined the involvement and impact of the CACNA1C rs1006737 risk SNP on cognitive functioning in the domains of executive functioning, working memory, and processing speed. Methods: A total of 70 euthymic BD-I participants and 76 healthy control (HC) participants were assessed on the cognitive domains of executive functioning, working memory, and processing speed and genotyped for the CACNA1C rs1006737 risk SNP. Results: No significant differences were observed in the scores for the cognitive domains of executive functioning, working memory, and processing between BD risk carriers vs. non-risk homozygotes, HC risk carriers vs. non-risk homozygotes, BD and HC risk carriers, and BD and HC non-risk homozygotes. Conclusion and Future Directions: The results suggest that the rs1006737 risk SNP does not have a significant impact on the cognitive domains investigated in BD and HC. However, our small sample size and lack of an age-matched control group are crucial limitations that must be taken into consideration. Future studies with larger sample sizes can help to further elucidate the role the CACNA1C rs1006737 risk SNP plays in cognitive functioning in BD. / Thesis / Master of Science (MSc)

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Bipolar Disorder (BD) is a debilitating mental illness that presents as mood alterations between manic and depressive states. There remain large gaps in the knowledge surrounding the disease, due to three main issues in understanding the illness. First is a lack of an appropriate animal model that mimics both manic and depressive symptoms. Second is a lack of knowledge on the biological cause of the disease. Finally, a lack of knowledge on the precise mechanism of action of lithium (Li), the main treatment for BD prevents more progressive research into the disease. Inflammation and a subsequent disruption of the blood-brain barrier (BBB) have recently been demonstrated in other psychiatric conditions, such as Alzheimer’s Disease (AD) and Schizophrenia (SZ). This mechanism remains to be fully investigated in BD. This thesis presents an inflammatory model of BBB disruption in rodents. A study examining gene expression in discordant sibling pairs with SZ or BD discovered that the Max gene was elevated two-fold in bipolar patients as compared to their non-BD siblings. We aim to elucidate on these findings and examine the effect of common BD treatments on Max gene expression. The first study utilized lipopolysaccharides (LPS) to induce an inflammatory response in the BBB, and sodium fluoroscein (NaF) to measure the levels of resulting disruption. It was shown that Li is unable to attenuate disruption of the BBB, and an LPS administration with Li pretreatment causes higher disruption than either substance alone in several brain regions. The second study examined Max gene expression levels in naïve rats as a result of Li or valproate (VPA) treatment. VPA was shown to significantly downregulate the expression of Max in a rodent model. These studies may provide insight into understanding the pathophysiology of BD, leading to better, more accurate animal models and more targeted therapies for the disorder. / Thesis / Master of Science (MSc)

Bipolar disorder (BD) is a chronic and often progressive illness that has a significant impact on quality of life and functioning. Pharmacological treatments are not effective for all patients, emphasizing the need to better understand the pathophysiology of the disorder. It is well known that patients with BD present with increased levels of inflammatory markers during mood episodes and often exhibit chronic low grade inflammation, implicating the immune system in the etiology of the disorder. Furthermore, patients with BD show deficits in neurotrophic factors suggesting that alterations in neurogenesis may precipitate clinical features. Recent evidence indicates that accelerated aging processes may underlie the pathophysiological changes observed in BD, implicating biomarkers related to aging. The chemokine C-C motif chemokine 11 (CCL11) and the cytokine growth differentiation factor 11 (GDF11) have been identified as proteins that increase and decrease with age, respectively. As such, this thesis presents research examining serum levels of these proteins in drug-naive young adults with BD and a matched healthy control group. We analyzed serum levels of CCL11 and GDF11 using enzyme linked immunosorbent assay (ELISA). Our results indicate that serum levels of CCL11 and GDF11 do not differ between the BD group and the healthy control group, however CCL11 levels were elevated in males and in individuals with tobacco abuse/dependence when considering the entire sample. Our results suggest that serum levels of these proteins do not differ between drug-naive young adults with BD and healthy controls, but that alterations may be due to demographic and lifestyle factors. Small sample size and low power should be considered when interpreting these results. / Thesis / Master of Science (MSc)

A Thesis Submitted to the School of Graduate Studies in Partial Fulfilment of the Requirements for the Degree Doctor of Philosophy in Neuroscience / Bipolar disorder (BD) is increasingly being recognized as a neuroprogressive illness characterized by progressively worsening cognitive function and structural brain changes. Although lithium remains the gold standard treatment for BD, its ability to halt neuroprogression is a crucial, yet not fully understood aspect of its therapeutic benefit. Accumulating evidence suggests that lithium may be neuroprotective through alleviating ER stress, a feature highly implicated in the pathogenesis of BD. Over the last 20 years, Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF), an ER resident protein, has gained significant attention due to its ability to alleviate ER stress, reduce inflammation, and enhance cellular survival. In this thesis, we investigated the relationship between lithium and MANF using in vitro cellular models and in vivo rodent models. We establish that lithium upregulates MANF expression via the AP-1 signalling pathway. Moreover, we show that MANF plays a crucial functional role in lithium’s neuroprotective effects, as inhibiting the AP-1 pathway negated lithium’s protection against ER stress-induced neurotoxicity and reduced MANF expression. Furthermore, we demonstrate that MANF deficiency increases striatal cell susceptibility to amphetamine-induced neurotoxicity, highlighting its protective function in preclinical models of mania. In vivo experiments further showed that overexpressing MANF in amphetamine-treated rats reduced hyperlocomotion, prevented the upregulation of ER stress markers, and prevented amphetamine-associated death. Collectively, these findings suggest that MANF may be a critical mediator of lithium’s ability to halt neuroprogression in BD and advance our understanding of BD pathophysiology. Importantly, we present MANF as a promising therapeutic candidate for future therapeutic interventions aimed at halting neuroprogression in BD and preventing fatality due to amphetamine overdose. / Dissertation / Doctor of Philosophy (PhD) / Bipolar disorder (BD) is a psychiatric condition characterized by extreme episodic mood swings of highs (mania) and severe lows (depression). Over time, BD patients can experience changes in the brain, worsening symptoms, and cognitive decline – a process understood as neuroprogression. Lithium, a common treatment for BD, has been shown to slow down this detrimental progression, although exactly how it is accomplished is not fully understood. This thesis focused on a protein called MANF, which has been shown to protect and keep brain cells healthy by reducing stress within cells. We found that lithium increases MANF levels in brain cells, and this increase is crucial for lithium’s neuroprotective effects. Furthermore, we show that MANF is protective against the toxic drug amphetamine in brain cells and stops overdose- mediated death from occurring. By understanding how MANF works, we propose a new treatment intended to prevent the progression of BD and potential treatment for amphetamine overdose.

Introduction: Bipolar disorder (BD) is a recurrent and chronic mood disorder. BD type I (BD-I) is associated with high disability, lower quality of life, and excess mortality. Importantly, BD is also associated with severe functional impairment. Staging models suggest BD is a progressive illness and use episode recurrence and functional impairment in euthymia as main proxy measures. Research has identified deficits in functioning in BD compared to healthy controls (HC) and suggest that impairment may be sustained in periods of euthymia and related to episode recurrence. The current research uses data from a larger longitudinal neuroimaging study to investigate psychosocial and subjective cognitive function, as measured by the Functional Assessment Short Test (FAST) and the Cognitive Failures Questionnaire (CFQ), in individuals with BD-I who experienced an episode relapse (BDR) compared to those who did not (BDNR) and healthy controls (HC). Methods: Participants completed up to 3 visits over 2 years, that took place approximately 1 year apart. The final sample consisted of 61 HC, 21 BDR, and 26 BDNR participants. Three analyses were conducted to explore between and within-subject differences: mixed-effects analysis of variance (ANOVA), one-way Kruskal-Wallis tests, and simple linear growth analyses. Missing data precluded using three time points for some analyses, so the mixed-effects ANOVA and one-way Kruskal-Wallis tests used two re-binned timepoints (baseline and follow-up) and the growth curve analysis used all three timepoints. Results: Significant differences were found between the HC group and both BD groups (BDR and BDNR) for both the FAST and CFQ at baseline and follow-up visits. No significant differences were found between the BDR and BDNR groups, neither differences at timepoints nor differences in change across timepoints. The BDNR group demonstrated a significant decrease in CFQ scores over the 3 timepoints. Conclusion and Future Directions: The results suggest that individuals with BD-I experience sustained impairment in psychosocial and subjective cognitive function over time compared to HC, but relapse does not have a significant effect on this impairment. Since the BDNR group demonstrated a decrease in CFQ scores over time, not experiencing relapse may be implicated in the improvement of subjective cognitive functioning. Future studies with longer measurement windows and larger sample sizes could further clarify these findings. / Thesis / Master of Science (MSc) / Bipolar disorder type I (BD-I) is a debilitating mood disorder involving manic episodes (e.g. heightened mood, excessive energy, impulsivity) and oftentimes depressive episodes as well (e.g. low mood, little interest in activities, sleep problems). BD-I is associated with high rates of functional impairment. Some models suggest that BD-I is a progressive illness wherein a longer duration of illness, a higher number of mood episodes, and lingering impairment at times outside of mood episodes can be indicators of the illness getting worse overtime and affecting individuals more negatively. Using data from a larger study, the current study aimed to investigate functional impairment in individuals with BD-I who experienced an episode relapse (BDR) compared to those who did not (BDNR) and healthy controls (HC). Two measures of function were used: psychosocial functioning was measured by the Functional Assessment Short Test (FAST) and subjective cognitive functioning was measured by the Cognitive Failures Questionnaire (CFQ). Participants completed up to 3 visits over 2 years, spaced approximately 1 year apart. Differences between both BD groups and the HC group were found for both scales, suggesting a sustained functional deficit in BD over time. No differences between the BDR and BDNR groups were found, but the BDNR group demonstrated improvement in subjective cognitive functioning over the 2-year period. These findings suggest that BD-I shows impairment in psychosocial and subjective cognitive functioning as compared to HC but that relapse status did not have an effect. This research suggests that perhaps mood episode relapse may not influence functioning negatively, but a lack of relapse may have positive effects on subjective cognitive functioning.

"Due to the high variation of critical device parameters inherent in integrated circuit manufacturing, modern integrated circuit designs have evolved to rely on the ratios of similar devices for their performance rather than on the absolute characteristics of any individual device. Today's high performance analog integrated circuits depend on the ability to make identical or matched devices. Circuits are designed using a tolerance based on the overall matching characteristics of their particular manufacturing process. Circuit designers also follow a general rule of thumb that larger devices offer better matching characteristics. This results in circuits that are over designed and circuit layouts that are generally larger than necessary. In this project we develop a model to predict the mismatch in a pair of NPN bipolar transistors. Precise prediction of device mismatch will result in more efficient circuit deigns, smaller circuit layouts and higher test yields, all of which lead to into more reliable and less expensive products."

Alteração da fosfolipase A2 tem sido descrita em diversas doenças neuropsiquiátricas. Esta enzima é responsável pelo metabolismo dos fosfolípides de membrana e parece estar envolvida na fisiopatologia do transtorno bipolar. Neste estudo, foram analisados os três principais subtipos da PLA2 (sPLA2, cPLA2 e iPLA2) em plaquetas de pacientes e indivíduos controles. A atividade de subtipos de PLA2 foi determinada em 20 pacientes TB sem tratamento com estabilizadores de humor e após seis semanas de tratamento com lítio; 72 pacientes medicados e 65 controles (16 pareados com os pacientes sem tratamento e 49 com os pacientes previamente medicados), pelo método radioenzimático. Os pacientes foram diagnosticados e classificados de acordo com os critérios estabelecidos no DSM-IV-TR. Foi verificado que Os pacientes no estágio inicial da doença apresentaram menor atividade de iPLA2, sPLA2 e cPLA2 quando comparadas ao grupo controle. Seis semanas de tratamento com o lítio não foram suficientes para observar alterações nos resultados obtidos. No entanto, o lítio diminuiu a sintomatologia maníaca e a depressiva, avaliadas pelas escalas de Hamilton e Young, respectivamente (p < 0,01 para as duas comparações). Os pacientes medicados não diferiram do grupo controle para os três subtipos de PLA2 avaliados. Estes resultados sugerem que no estágio inicial do TB há uma diminuição da atividade das PLA2, e que a ação de um ou mais medicamentos que são incluídos na terapêutica para este transtorno podem reverter essa diminuição. Sugere-se ainda que a diminuição da atividade da iPLA2 no estágio inicial do transtorno bipolar, além de alterar o remodelamento da membrana, possa ser um fator de risco para o desenvolvimento de demência nestes pacientes. / Changes in phospholipase A2 have been reported in several psychiatric disorders. This enzyme is responsible for the metabolism of membrane phospholipids and has been suggested to play a role in bipolar disorder physiopathology. In this study, the activity of the three main subtypes of phospholipase A2 (PLA2) were analyzed (sPLA2, cPLA2 and iPLA2) in platelets of BD patients and health subjects. Subjects enrolled were: 20 drug-naïve and drug free BD patients, who were treated with lithium for six weeks; 72 BD long-term treatment patients and 65 controls (16 for the drug-naïve and drug free and 49 for the long term group). PLA2 subtype activities were determined by the radio enzymatic method. Patients\' diagnostic and classification were made according to DSM-IV-TR criteria. Patients at the early stage of the disease presented lower iPLA2, sPLA2 and cPLA2 activity than the control group. Six weeks treatment with lithium did not change these activities. However, lithium reduced the maniac and depressive symptoms, evaluated with Hamilton and Young scales, respectively (p < 0.01, for both comparisons). Long-term treated patients presented similar PLA2 activities to control group. The results suggest that at the early stage of BD iPLA2 activity is decreased and that the adequate treatment of BD could reverse this reduction. We suggest that a reduction of iPLA2 activity at the early stage of BD can modify the membrane metabolism, and could be a risk for the development of dementia in BD patients.

O Transtorno Afetivo Bipolar (TAB) é um transtorno mental crônico e recorrente. Está situado entre as principais doenças que causam incapacitação e morbidade em todo mundo. A substituição do modelo de atendimento ao doente mental centrado no hospital, por uma rede de serviços prestados na comunidade, tem como conseqüência o aumento do número de pacientes vivendo em família. Estas famílias são solicitadas a oferecer apoio emocional, tolerar estigma, lidar com perdas financeiras e laboral, interrupções na rotina do lar, entre outras. Tais implicações correspondem à sobrecarga que são as conseqüências que o familiar enfrenta ao conviver com pessoa portadora de transtorno mental. O objetivo deste estudo foi identificar e descrever a sobrecarga do TAB nas famílias que convivem com algum portador deste transtorno. Foram entrevistados 15 familiares, sendo três filhos, quatro irmãs, duas cunhadas, uma ex- cunhada, três cônjuges, uma tia e uma mãe. Foram utilizados para a coleta de dados um questionário com informações sobre dados clínicos do paciente com TAB, Critério Padrão de Classificação Econômica Brasil 2008 e roteiro de entrevista semi-estruturado adaptado por Koga (1997) que engloba a sobrecarga familiar. As respostas foram analisadas utilizando-se a técnica de análise de conteúdo de Bardin. O impacto do TAB sobre a família foi descrito nos seguintes aspectos: trabalho, gastos, lazer, relacionamento interpessoal, futuro, recursos e adoecimento do familiar como expressão de sobrecarga. Observou-se que a família se sente mais sobrecarregada nos períodos de crise da doença. Nos períodos estáveis somente os aspectos trabalho e relacionamento interpessoal permanecem como ponto de preocupação e sofrimento familiar. O fato de não se conhecer as causas e tampouco a cura, faz com que apareçam insegurança e temor quanto ao futuro. Este estudo contribuiu para compreender que TAB também sobrecarrega a família que necessita e solicita apoio dos profissionais de saúde para obter melhora na qualidade de vida. A principal limitação do presente estudo é o número pequeno de familiares entrevistados e o fato de todos terem sido recrutados em um único serviço de saúde. Pesquisas semelhantes deverão ser realizadas a fim de verificar se outras famílias manifestam sobrecarga semelhante as apresentadas pelos familiares deste estudo. / The bipolar disorder (BD) is a chronic and recurring mental disorder. Nowadays, it is one of most important disease that is responsible for incapacity and morbidity worldwide. The replacement treatment model of mental illness that was focus at hospital for services accessible to community is responsible for increase of number of patients living in family contexts. These families are responsible to offer emotional support, sometimes tolerate stigma, deal with financial and work loses, disruption at home routine and other ones. These implications are the result of relationship with a person with mental illness. The aim of this study was to identify and describe the burden of bipolar disorder in the family that lives with a person that has this disorder. Questioners were applied for fifteen relatives: tree children, four sisters, tree sistersin- law, tree spouse, 1 aunt and 1 mother. The data were collected using questionnaires with information about clinic data of BD patients, Standard Economic Classification Brazil 2008 and semi structured interview adapted by Koga. The results were analyzed by Bardins content technique. The impact in the family resulting of the relationship with BD patients was described following these aspects: work, costs with daily life, leisure, interpersonal relationship, future, resource and falling ill like expression of burden. As a result BD patients family reported that they were burdensome in the severe periods of disease. In the stable periods, only work and interpersonal aspects are continuous factors of worry and familiar suffer. Ignore the causes and the cure emerge insecurity and fear about the future. This study contributed to comprehension of that BD also burdensome the family of the patients. In addition, this people require support of health professionals to provide quality of life. The limits of this study were the short number of relatives submitted to questioners and they were come from the one source. More studies will be necessary to analyze other families and the pattern of BD illness burdensome.